This book review originally appeared in Development. Lance Davidson reviews “Mathematical Models of Biological Systems” (by Hugo van den Berg).

Book info:
Mathematical Models of Biological Systems By Hugo van den Berg Oxford University Press (2010) 256 pages ISBN 978-0-19-958218-1 (paperback), 978-0-19-958219-8 (hardback) £27.50/$49.50 (paperback), £65/$117 (hardback)

One of the key goals of modern cell and developmental biology is to expose the underlying principles that drive cell differentiation and to elucidate how organisms construct functional multicellular structures. Thanks to advances in sequencing, high throughput screens and sophisticated imaging technologies, these fields are now awash with quantitative descriptions of gene transcription, cell signaling and cell mechanics. However, extracting key principles from the flood of new data is a major challenge for researchers and a central obstacle to fundamental progress in cell and developmental biology. The tools required to interpret this vast amount of biological data and to test hypotheses based on these studies can be found in quantitative analysis and mathematical modeling. With the book Mathematical Models of Biological Systems, Hugo van den Berg aims to contribute to the training of a new generation of biologists and mathematicians and to provide them with an introduction to the methods that are now available to quantitatively analyze biological data.

Like many quantitative biologists, my first exposure to mathematical modeling was not in the context of cell biology or developmental biology, but came through examples from physical chemistry, physiology and population ecology. In these fields, simple problems can be formulated using ordinary differential equations (ODEs) with complete statements of the state variables, such as initial conditions. As students, we learned to write ‘word-models’ and to translate these into sets of ODEs. Word models are narrative passages intended to translate the details of a biological problem such that biologists and mathematicians alike can understand the problem in a way that allows equations to be written which capture those details. For instance, we can distil the interactions between predators and prey by stating the rules that govern their populations. Rules that govern the population of prey might include sources of population growth, such as birth or migration, and losses to the population due to predation or disease. The precise statement of these rules should be complete enough to govern the mathematical formulation of the model. Given a well-defined word model, the mathematical biologist can then write a series of ODEs; for example, with variables that represent the number of predators and prey and equations to describe how populations of predators and prey change. As students, we sometimes discovered that there were closed form solutions of these ODEs, in which changes in variables can be predicted explicitly by equations. But more often we found that we could only evaluate the general dynamic behavior of the variables; for instance, whether populations of predators and prey are stable or not. The insights and training that these model-building exercises gave us were instrumental in becoming fluent in the basic skills of mathematical modeling. The processes of formulating a model and relating fundamental principles to the mathematics and experimental outcomes were often more informative than the solution itself. However, after marveling at the awesome power of ODEs, we soon realized that the solution of some, or indeed most sets of, ODEs was intractable, that there was no way to capture relevant details of complex biology with continuous variables, or that model predictions could not be tested experimentally. As such, the tool kit of ODEs used to learn the skills of mathematical modeling is less useful for developing the quantitative models that are needed to describe problems in cell and developmental biology.

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Dates for your calendar
This is a selection of upcoming dates of interest, but it’s by no means an exhaustive list. We’ll try to do these once in a while, but don’t hesitate to write your own posts to let people know about similar deadlines, or leave a comment below. Also make sure to check eligibility before applying.

Conference Registration now open:
–ISSCR meeting (June 13-16, 2012)
–BSDB meeting (April 15-18, 2012)
–LASDB meeting (April 26-29, 2012) – early deadline closes December 12!
-Keystone: The Life of a Stem Cell: From Birth to Death (Mar 11-16, 2012) – early deadline closes January 11, Abstract deadline closes December 13.
-Keystone: Non-Coding RNAs with Eukaryotic Transcription (Mar 31-Apr 5, 2012) – early deadline closes January 30, Abstract deadline closes January 5
-EMBO: Plant development and environmental interactions (27 – 30 May, 2012) – registration and abstract submission closes February 15.
-EMBO: 30 Years of Wnt Signaling (27 June – 1 July, 2012) – Pre-registration & abstract submission deadline: 29 February 2012

Courses:
-SDB-LASDB 4th PASI short course A Systems Biology Approach to Understanding Mechanisms of Organismal Evolution
April 16-25, 2012 in Montevideo, Uruguay (Note, this is right before the LASDB conference at the same location.)
Application deadline is December 15, 2011
-EMBO Practical Course in Advanced Optical Microscopy (March 21-31, 2012) – General application deadline Friday 20 January 2012. Deadline for visa-dependent students 31 December 2011
-EMBO Laboratory Management Courses for postdocs and for independent group leaders. Held at various times during the year in the UK and Germany. Still spots left at some of the courses.
-For those of you in or near the UK, the Royal Society is hosting several Media and Communication Skills Courses for scientists.

Travel fellowships:
-The next round of The Company of Biologists travel fellowships closes December 31st. The funds can be used for a short research exchange in another lab. Postdocs and PhD students (from all countries) can apply.

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This book review originally appeared in Development. Ilan Davis reviews “Molecular Biology of RNA” (by David Elliot and Michael Ladomery).

Book info:
Molecular Biology of RNA By David Elliot, Michael Ladomery Oxford University Press (2010) 460 pages ISBN 978-0-19-928837-3 £34.99/$55 (paperback)

Following the discovery of the structure of DNA and during the early days of molecular biology, RNA was considered to be a less interesting cellular component to study than DNA. This was primarily because RNA was thought to be simply a molecular photocopy of the genetic blue print stored in DNA. But how things have changed! Since those early days, our understanding of the cellular roles of RNA has changed radically. RNA is now considered to be of central importance to both molecular biology and cellular function. Far from only containing genetic information, RNA is now regarded to have credible catalytic properties through the availability of its 2′-OH, a reactive group that replaces a non-reactive ‘O’ atom in DNA. Moreover, its catalytic roles include key functions in the most important molecular machines of the cell, such as the spliceosome and ribosome. In hindsight, it would perhaps not be so surprising if the RNA world hypothesis turned out to be correct. This hypothesis states that the first life forms on our planet were RNA-based simple cells in the pre-biotic soup. RNA is certainly a better candidate than either DNA or proteins for a self-replicating molecule that acts both as a template for, and that has the necessary catalytic machinery to perform, its own replication. Moreover, the discovery that most mRNAs are spliced, and the gradual uncovering of a breathtaking number of ways in which gene expression is regulated post-transcriptionally, have meant that the field of RNA has undergone rapid growth in the past few decades. This rapid growth has recently increased even further because of the discovery of RNA interference (RNAi), as well as the discovery that small RNAs, distinct from tRNA and snRNA, undergo processing to fulfil a range of cellular functions. These include the regulation of transposable element transposition by piRNAs, regulation of translation by microRNAs and still poorly explored large non-coding RNAs (ncRNA). Many of these ncRNAs have turned out to have important roles in development and during disease processes, such as cancer. Therefore, it is clear that all aspects of RNA molecular biology have now become central to our understanding of cell and developmental biology.

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Satellite cells are muscle stem cells that regenerate injured muscle (remember this earlier post?).  They are highly motile cells that may be able to travel in order to repair injured muscle far away, and a recent paper in Development describes the role of Eph/ephrin signaling in satellite cell motility and patterning.

One of the most well-understood guidance pathways is the Eph/ephrin pathway, which has major roles in cell migration and axon guidance throughout development.  In this pathway, Eph receptors on one cell interact with ephrin ligands bound to another cell’s membrane.  This interaction typically causes rapid changes in the Eph-expressing cell’s adhesion and cytoskeletal organization, and frequently causes the cells to repel each other.  A recent paper describes the role of Eph/ephrin signaling in satellite cell motility and patterning.  Stark and colleagues showed that ephrin ligands are differentially localized to healthy and regenerating muscle tissue, and used a well-established “stripe assay” to show that ephrins can repel mouse satellite cells.  As seen in the images above (increasing magnification from left to right), stripes of ephrin-B1 ligand (bottom row, blue stripes) repulsed the satellite cells, compared to the distribution of cells on control stripes (top row).  In addition, Stark and colleagues explanted mouse satellite cells into the hindbrain of developing quail embryos, from which neural crest cells emigrate using Eph/ephrin signaling.  Some satellite cells migrated along with the neural crest cells and conformed to the same boundaries.

For a more general description of this image, see my imaging blog within EuroStemCell, the European stem cell portal.

Stark, D., Karvas, R., Siegel, A., & Cornelison, D. (2011). Eph/ephrin interactions modulate muscle satellite cell motility and patterning Development, 138 (24), 5279-5289 DOI: 10.1242/dev.068411

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Here are the highlights from the current issue of Development:

Notching up pancreas development

According to the lateral inhibition model, during early pancreas development, Neurog3 expression in multipotent progenitor cells (MPCs) initiates endocrine differentiation and activates expression of the Notch ligand Dll1. Dll1 then activates Notch receptors in neighbouring cells, which turns on Hes1 expression. Finally, Hes1 inhibits Neurog3 expression in these neighbouring cells, thereby preventing excessive endocrine differentiation. On p. 33, Palle Serup and colleagues challenge this model by showing that Dll1, Hes1 and Dll1/Hes1 mutant phenotypes diverge at key points of mouse pancreas development. Moreover, pancreatic hypoplasia in Dll1 mutants is independent of endocrine development and is not, therefore, caused by excessive endocrine differentiation and progenitor depletion, as previously believed. Instead, the researchers report, reduced MPC proliferation is responsible for this hypoplasia. Other results indicate that Ptf1a (pancreas transcription factor 1 subunit α) activates Dll1 expression and that Hes1 sustains Ptf1a expression and Dll1 expression in early MPCs. Thus, Ptf1a-mediated control of Dll1 expression, rather than a lateral inhibition mechanism, is crucial for Notch-mediated control of early pancreas development.

Modelling stem cell population dynamics

Many tissues and organs are maintained by stem cell populations. Anatomical constraints, cell proliferation dynamics and cell fate specification all affect stem cell behaviour, but their relative effects are difficult to examine in vivo. E. Jane Albert Hubbard, Hillel Kugler and colleagues now use available data to build a computational model of germline development in C. elegans (see p. 47). In this model, germline cells move, divide, respond to signals, progress through mitosis and meiosis, and differentiate according to various local rules. Simulations driven by the model recapitulate C. elegans germline development and the effects of various genetic manipulations. Moreover, the model can be used to make new predictions about stem cell population dynamics. For example, it predicts that early cell cycle defects may later influence maintenance of the progenitor cell population, an unexpected prediction that the researchers validate in vivo. This general modelling approach could, therefore, prove to be a powerful tool for increasing our understanding of stem cell population dynamics.

Time and place generate neuronal diversity

The spinal cord contains many distinct interneuron cell types that have specialised roles in somatosensory perception and motor control. How this neuronal diversity is generated from multipotent progenitor cells is unclear. Here (p. 179), Martyn Goulding and colleagues investigate the differentiation of Renshaw cells, one of the spinal interneuron subtypes that arises from the spatially defined V1 class of interneurons. They show that the first-born postmitotic V1 interneurons are committed to the Renshaw cell fate. This fate, they report, is determined by a temporal transcriptional program that involves selective activation of the Oc1 and Oc2 transcription factors during the first wave of V1 interneuron neurogenesis, broader expression of the Foxd3 transcription factor in postmitotic V1 interneurons, and later expression of the MafB transcription factor. Importantly, Renshaw cell specification and differentiation proceeds normally in the absence of neuronal activity. Overall, these results suggest that a combination of spatial and temporal determinants might be the major mechanism for generating neuronal diversity in the spinal cord.

Topsy-turvy cilia precede neural progenitor delamination

During the development of the mammalian cerebral cortex, basal progenitor cells delaminate from the apical adherens junction belt of the neuroepithelium. But what are the cell biological processes that precede the delamination of these neural progenitors? On p. 95, Wieland Huttner and co-workers identify a new pre-delamination state of neuroepithelial cells in the mouse embryonic neocortex. Using electron microscopy, the researchers show that, in a subpopulation of neuroepithelial cells, the re-establishment of the primary cilium after mitosis occurs at the basolateral rather than at the apical plasma membrane. Neuroepithelial cells carrying basolateral cilia selectively express the basal progenitor marker Tbr2, they report, and delaminate from the apical adherens junction belt to become basal progenitors. Notably, overexpression of insulinoma-associated 1, a transcription factor that promotes the generation of basal progenitors, increases the proportion of neuroepithelial cells with basolateral cilia. Together, these results suggest that the re-establishment of a basolateral primary cilium is a cell biological feature that precedes neural progenitor delamination.

Digging into Polycomb repression

Polycomb group proteins control diverse developmental processes by repressing the transcription of developmental regulator genes through chromatin modification. The Drosophila Polycomb repressive complex 1 (PRC1), which contains the four core subunits Sce (Sex combs extra), Psc (Posterior sex combs), Ph (Polyhomeotic) and Pc (Polycomb), exhibits two chromatin-modifying activities – H2A monoubiquitylation and chromatin compaction. Here (p. 117), Jürg Müller and co-workers provide new insights into PRC1-mediated transcriptional repression. The researchers show that Sce is the major H2A ubiquitylase in Drosophila and identify the genes that are bound by PRC1. Then, by analysing mutants that lack individual PRC1 subunits, they identify two classes of PRC1 target genes. Repression of class I genes requires all four PRC1 core subunits whereas repression of class II genes requires only Psc and Ph. The researchers suggest, therefore, that H2A monoubiquitylation is crucial for the repression of a subset of PRC1 target genes but that chromatin compaction mediated by Psc and Ph may be the major mechanism by which PRC1 represses other target genes.

Gβγ signals polarise primordial germ cells

Directed cell migration occurs many times during embryogenesis. For example, in many species, primordial germ cells (PGCs) migrate after specification to the site of the future gonad. This migration involves PGC polarisation and PGC responsiveness to external guidance cues. In zebrafish, the chemokine Cxcl12a regulates directed migration, whereas the Rho GTPase Rac1 regulates polarisation. But what controls Rac activity? Fang Lin and co-workers now report that signalling mediated by the G protein subunits Gβ and Gγ (Gβγ) regulates Rac activity in zebrafish PGCs (see p. 57). The researchers show that PGCs defective for Gβγ signalling, like those with reduced Rac activity, fail to polarise and fail to migrate actively in response to directional cues. They also show that PGCs require Gβγ signalling for polarised activation of Rac and for maintenance of their overall Rac levels. These and other results suggest that, during PGC migration in zebrafish, Gβγ signalling regulates Rac activity to control the cell polarity that is needed for PGC responsiveness to chemokine signalling.

Plus…

Cell fate decisions and axis determination in the early mouse embryo

The mouse embryo generates multiple cell lineages, as well as its future body axes in the early phase of its development. Here, Takaoka and Hamada address the timing of the first cell fate decisions and of the establishment of embryonic polarity, and ask how far back one can trace their origins.

See the Review article on p. 3

Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells

During mouse development, the epigenetic states of pre-implantation embryos and primordial germ cells undergo extensive reprogramming. Recent studies of DNA demethylation dynamics, reviewed by Saitou, Kagiwada and Kurimoto, provide new insights into the regulation of these epigenetic states. See the Review article on p. 15

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Ever noticed how each field has its own jargon?

Benchfly, a site with free video protocols and other resources for researchers, has created “Group Meeting Bingo”. The site generates bingo cards with the particular phrases common to various fields of research. They have cards for biochemistry, cell biology, and various other fields, but no developmental biology…yet!

So, let’s make a developmental biology bingo game!

Over the next few weeks (until we have enough words), you can leave a comment below (no registration required) with your suggestions for typical words that regularly show up in developmental biology talks. Benchfly will then turn our suggestions into a playable bingo game!

They suggest taking out the cards during meetings, but I’ve enjoyed just refreshing the existing cards on the site and marveling at all the field-specific words.

Section of one of the cell biology bingo cards. Of course some of the words from other fields can appear on the developmental biology cards as well!

Looking forward to see what you all come up with for the developmental biology game!

NB: The Node does not endorse playing bingo at the expense of paying attention to talks. Personally I’ve played a similar game at a conference where the meeting organizers handed out the cards, and encouraged everyone to play. I found it very easy to pay attention to the talks there, take notes, learn things, and still win the game. It’s actually easier to spot the words if you are paying attention!

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In 2007, a group let by Takahashi and Yamanaka from Kyoto University successfully generated pluripotent cells from human adult fibroblasts.  They were able to induce a pluripotent state in differentiated cells by introducing four transcription factors, OCT4, SOX2, c-MYC, and KLF4 by retroviral infection, hence the name “induced pluripotent stem cells (iPSCs).”  Although the mechanism of how these factors induced pluripotency in somatic cells is not completely understood, it is clear that the endogenous pluripotency genes OCT4, SOX2 and NANOG were activated and, in turn, re-activated the autoregulatory loop that could maintain the pluripotent state independent of the transgenes. iPS cells showed many characteristics of human embryonic stem cells (hESCs) such as expression of pluripotency markers, reactivation of telomerase and the ability to form teratomas, demonstrating a potential to redifferentiate into descendants of all three embryonic lineages.

However, follow-up studies suggested that the reprogramming of iPS cells was incomplete. Some epigenetic imprinting remained, the telomeres length was not fully restored, and the descendants of these cells entered senescence prematurely. Additionally, it was reported that cells from older donors were difficult to convert to iPS cells.

As people age the number of cells that are senescent increases.  Senescence is defined as an irreversible cell proliferation arrest and occurs in response to various stresses, including activation of oncogenes, shortened telomeres, DNA damage, oxidative stress and mitochondrial dysfunction.  Common features of senescence include activation of the p53/p21 and p16^/pRb pathways and formation of senescence-associated heterochromatic foci (SAHF).

Conversion of somatic cells to iPS cells occurs at very low frequency in any given cell population, but because older individuals have a higher number of senescent cells it has proved to be difficult to convert cells from older-aged donors. In an effort to overcome this barrier some researchers tried an alternative four-factor combination, substituting NANOG and LIN28 for c-MYC and KLF4, but without much improvement. Researchers began to wonder whether cellular aging was a barrier to iPS cell conversion.

In a recent paper published the November issue of Genes in Development, entitled “Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state,” Lapasset and colleagues from the Institute of Functional Genomics in France report that they have overcome this barrier and generated iPS cells from human donors as old as 101 years.  What’s more, the converted cells showed no signs of premature aging and appeared “rejuvenated” – iPS cells converted from nearly senescent donor cells regained their replicative potential and, when re-differentiated to fibroblasts, by all accounts resembled young proliferative cells.

The key was to use six transcription factors, not four, combining OCT4, SOX2, c-MYC, KLF4, NANOG and LIN28. Initially, they took fibroblasts from a 74-year-old man and induced them into replicative senescence by serial passaging. Senescence was confirmed by FACS analysis showing cell cycle arrest, increase in molecular markers characteristic of senescence, and formation of SAHF.

The six transcription factors were introduced by lentiviral infection. A week after infection,  the SAHF disappeared (see figure above, left panel) and after 40 days colonies appeared that looked like hES cells (see figure above, right panel). Lapasset et al. examined individual clones and found that endogenous pluripotency gene expression was activated and the promoters of OCT4 and NANOG, which are usually heavily methylated in differentiated cells, were demethylated in the newly converted iPS cells.  Individual clones were able to differentiate into cells expressing markers of all three germ layers as well as form teratomas with organ-like structures typical of all three embryonic lineages.

The authors then repeated this procedure with cells from donors 92, 94, 96 and 101 years of age and again were successful in generating iPS cells with the same efficiency, making these the oldest human donors so far whose cells were reprogrammed for pluripotency.

They extensively tested whether the iPS cells retained marks of aging similar to cells they originated from. They found that unlike parental cells, p16 and p21 expression in iPS cells was downregulated, similar to hES cells.  Additionally, telomere length was restored and maintained after numerous population doublings.  Because previous reports using the 4-factor induction method reported that iPS cells induced from  aged donor cells have chromosomal abnormalities the authors examined the karyotypes of the iPS, but found that in all cases they were normal.

They went on to compare the transcriptomes of the iPS cells with those of the hES cells and the parental cell types. The result was that the iPS cells gene expression profile had much more in common with hES cells and very little with the parental cells.

The final question they addressed was whether reprogramming of senescent cells and cells from long-lived donors to a pluripotent state leads to the production of “young” cells upon redifferentiation. Previous studies of fibroblasts derived from iPS cells showed that they have limited replicative potential and entered senescence early. In this study, when the iPS cells derived from 74-year-old and 96-year-old donors were redifferentiated to fibroblasts their rate of proliferation was similar to young proliferative fibroblasts.  The cells had regained replicative potential and were able to go through additional 60 population doublings before re-entering senescence, in contract to the sencescent cells they were derived from, which were no longer capable of replicating.

Transcriptome analysis of the newly differentiated fibroblasts showed that they resembled young proliferative embryonic fibroblasts derived from hES cells rather than their parental cell types. They also had less oxidative stress and better mitochondrial function than the parental cells.  The authors concluded that the cells were “rejuvenated” as a result of reprogramming through the pluripotent state.

This paper represents a significant advance in the field of iPS cells, demonstrating that cellular aging is not a barrier to generating pluripotent cells, bringing us one step closer to cell-based therapies for aged patients.

Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, Leschik J, Pellestor F, Ramirez JM, De Vos J, Lehmann S, & Lemaitre JM (2011). Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes & development, 25 (21), 2248-53 PMID: 22056670

(3 votes)

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This book review originally appeared in Development. Richard Harland reviews the latest edition of “Principles of Development” (by Lewis Wolpert and Cheryll Tickle).

Book info:
Principles of Development By Lewis Wolpert, Cheryll Tickle Oxford University Press (2011) 656 pages ISBN 978-0-19-954907-8 £36.99 (paperback)

What is to be taught in an undergraduate course on developmental biology? As in all branches of biology, there is far too much known to be able to teach it all, and any introductory course would sacrifice depth. Inevitably, choices must be made, and one choice is to emphasize important principles and concepts of development across all organisms. Lewis Wolpert and Cheryll Tickle, with a cast of impressive supporting authors, have made excellent selections in Principles of Development. This is the fourth edition of the book and the thoughtful choice of topics that went into the first edition is still evident, although there have also been many useful updates.

The book begins with some history and a summary of general concepts. The concepts are important ones, especially when framed by the title of the book, but they may be a little dry out of the context of real organisms. However, one has to start somewhere, and the general concepts are illustrated in later chapters with examples from real animals and plants. The principles and concepts could be re-stated more forcefully throughout the book, though, as they may be missed by the inattentive reader. Along the way, boxes explain the important experimental techniques that provide approaches to questions. The figures are drawn in a consistent style, which helps to give a coherent presentation and lets the student focus on content. Although the images are variants of the kinds of drawings we have seen in original journal articles and other textbooks, they are rendered here with style and clarity. The photographs are usually well chosen, though in some cases they don’t seem to be as clear or as relevant as they should be. For example, it isn’t clear why a well-camouflaged California false hellebore, the source of the teratogen cyclopamine, is shown, rather than the (admittedly grisly) cyclopic consequences of its action.

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I’m the new Executive Editor at Development, taking over after Jane Alfred’s eight years at the journal, and I’d like to take this opportunity to introduce myself. I’m starting here fresh off the plane from Heidelberg, Germany, where I have been working as a scientific editor at The EMBO Journal for the last three years, handling manuscripts in the fields of developmental and cell biology. Before then, my research life is probably best described as “trying to understand how to make an eye”: firstly during my PhD with Matthew Freeman at the Laboratory of Molecular Biology in Cambridge working with Drosophila (where I published my first ever paper in Development!), and subsequently studying morphogenesis of the fish retina in Jochen Wittbrodt’s lab at EMBL Heidelberg.

While I’m no longer in the lab, I’m still fascinated by the subject, and am excited to be getting back to my developmental biologist roots here at the journal. To me, Development is all about publishing by and for the community, and The Node is a big part of that: I’ve been reading it since its inception last year, and I look forward to playing a more active role from now on – I’m sure you’ll be hearing more from me in the future. I also hope to be meeting many of you in person over the coming months and years. For now, though, all that remains is for me to thank Jane for the fantastic job she’s done here: I have big boots to fill, but I hope I’m up to the challenge!

(8 votes)

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